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1.
BMC Pulm Med ; 21(1): 338, 2021 Oct 29.
Article in English | MEDLINE | ID: covidwho-1486570

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) accompanies hypercytokinemia, similar to secondary hemophagocytic lymphohistiocytosis (sHLH). We aimed to find if HScore could predict disease severity in COVID-19. HScore was calculated in hospitalized children and adult patients with a proven diagnosis of COVID-19. The need for intensive care unit (ICU), hospital length of stay (LOS), and in-hospital mortality were recorded. The median HScore was 43.0 (IQR 0.0-63.0), which was higher in those who needed ICU care (59.7, 95% CI 46.4-72.7) compared to those admitted to non-ICU medical wards (38.8, 95% CI 32.2-45.4; P = 0.003). It was also significantly higher in patients who died of COVID-19 (105.1, 95% CI 53.7-156.5) than individuals who survived (41.5, 95% CI 35.8-47.1; P = 0.005). Multivariable logistic regression analysis revealed that higher HScore was associated with a higher risk of ICU admission (adjusted OR = 4.93, 95% CI 1.5-16.17, P = 0.008). The risk of death increased by 20% for every ten units increase in HScore (adjusted OR 1.02, 95% CI 1.00-1.04, P = 0.009). Time to discharge was statistically longer in high HScore levels than low levels (HR = 0.41, 95% CI 0.24-0.69). HScore is much lower in patients with severe COVID-19 than sHLH. Higher HScore is associated with more ICU admission, more extended hospitalization, and a higher mortality rate. A modified HScore with a new cut-off seems more practical in predicting disease severity in patients with severe COVID-19.


Subject(s)
COVID-19/diagnosis , Severity of Illness Index , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/mortality , COVID-19/pathology , COVID-19/therapy , COVID-19 Testing , Child , Child, Preschool , Critical Care/statistics & numerical data , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/virology , Female , Hospital Mortality , Hospitalization , Humans , Infant , Iran/epidemiology , Length of Stay/statistics & numerical data , Logistic Models , Male , Middle Aged , Predictive Value of Tests , Prognosis , Prospective Studies , Survival Analysis , Young Adult
2.
BMC Infect Dis ; 21(1): 811, 2021 Aug 13.
Article in English | MEDLINE | ID: covidwho-1477276

ABSTRACT

BACKGROUND: Hemophagocytic syndrome (HPS) is a severe hyperinflammatory disease, whose diagnosis is based on the HLH-2004 criteria. In secondary forms of HLH (sHLH), the primary goal is treating the triggering factors such as COVID-19 (Coronavirus disease 2019). The link between the cytokine storm related to COVID-19 and development of sHLH has already been reported since the onset of pandemic, but little is known about clinical manifestations of HLH which develop after the patient's recovery from mild symptomatic or asymptomatic Sars-CoV-2 infection. CASE PRESENTATION: We describe the case of a woman diagnosed with sHLH related to previous Sars-CoV-2 infection and successfully treated with steroids, colchicine, etoposide and ruxolitinib. CONCLUSIONS: Our report suggests that HLH-like syndrome might be secondary to Sars-CoV-2 infection, even if the patient utterly recovered from the mildly symptomatic viral infection. In addition, we underline the treatment with low dose ruxolitinib plus etoposide as a potential choice for Sars-CoV-2 infection related HLH.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/diagnosis , Lymphohistiocytosis, Hemophagocytic/diagnosis , COVID-19/diagnosis , Cytokine Release Syndrome/etiology , Female , Humans , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/etiology , Middle Aged , Pandemics , SARS-CoV-2
5.
Front Immunol ; 12: 659419, 2021.
Article in English | MEDLINE | ID: covidwho-1389180

ABSTRACT

Highly pathogenic virus infections usually trigger cytokine storms, which may have adverse effects on vital organs and result in high mortalities. The two cytokines interleukin (IL)-4 and interferon (IFN)-γ play key roles in the generation and regulation of cytokine storms. However, it is still unclear whether the cytokine with the largest induction amplitude is the same under different virus infections. It is unknown which is the most critical and whether there are any mathematical formulas that can fit the changing rules of cytokines. Three coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2), three influenza viruses (2009H1N1, H5N1 and H7N9), Ebola virus, human immunodeficiency virus, dengue virus, Zika virus, West Nile virus, hepatitis B virus, hepatitis C virus, and enterovirus 71 were included in this analysis. We retrieved the cytokine fold change (FC), viral load, and clearance rate data from these highly pathogenic virus infections in humans and analyzed the correlations among them. Our analysis showed that interferon-inducible protein (IP)-10, IL-6, IL-8 and IL-17 are the most common cytokines with the largest induction amplitudes. Equations were obtained: the maximum induced cytokine (max) FC = IFN-γ FC × (IFN-γ FC/IL-4 FC) (if IFN-γ FC/IL-4 FC > 1); max FC = IL-4 FC (if IFN-γ FC/IL-4 FC < 1). For IFN-γ-inducible infections, 1.30 × log2 (IFN-γ FC) = log10 (viral load) - 2.48 - 2.83 × (clearance rate). The clinical relevance of cytokines and their antagonists is also discussed.


Subject(s)
Cytokine Release Syndrome/immunology , Cytokines/blood , Models, Immunological , Virus Diseases/complications , Biomarkers/blood , Biomarkers/metabolism , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Viral Load/immunology , Virus Diseases/blood , Virus Diseases/immunology , Virus Diseases/virology
6.
J Am Heart Assoc ; 10(16): e021428, 2021 08 17.
Article in English | MEDLINE | ID: covidwho-1348207

ABSTRACT

Background Cardiac dysfunction is a prominent feature of multisystem inflammatory syndrome in children (MIS-C), yet the etiology is poorly understood. We determined whether dysfunction is global or regional, and whether it is associated with the cytokine milieu, microangiopathy, or severity of shock. Methods and Results We analyzed echocardiographic parameters of myocardial deformation and compared global and segmental left ventricular strain between 43 cases with MIS-C ≤18 years old and 40 controls. Primary outcomes included left ventricular global longitudinal strain, right ventricular free wall strain), and left atrial strain. We evaluated relationships between strain and profiles of 10 proinflammatory cytokines, microangiopathic features (soluble C5b9), and vasoactive-inotropic requirements. Compared with controls, cases with MIS-C had significant impairments in all parameters of systolic and diastolic function. 65% of cases with MIS-C had abnormal left ventricular function (|global longitudinal strain|<17%), although elevations of cytokines were modest. All left ventricular segments were involved, without apical or basal dominance to suggest acute stress cardiomyopathy. Worse global longitudinal strain correlated with higher ratios of interleukin-6 (ρ -0.43) and interleukin-8 (ρ -0.43) to total hypercytokinemia, but not absolute levels of interleukin-6 or interleukin-8, or total hypercytokinemia. Similarly, worse right ventricular free wall strain correlated with higher relative interleukin-8 expression (ρ -0.59). There were no significant associations between function and microangiopathy or vasoactive-inotropic requirements. Conclusions Myocardial function is globally decreased in MIS-C and not explained by acute stress cardiomyopathy. Cardiac dysfunction may be driven by the relative skew of the immune response toward interleukin-6 and interleukin-8 pathways, more so than degree of hyperinflammation, refining the current paradigm of myocardial involvement in MIS-C.


Subject(s)
Atrial Function, Left , COVID-19/complications , Cytokine Release Syndrome/etiology , Cytokines/blood , Heart Diseases/etiology , Inflammation Mediators/blood , Systemic Inflammatory Response Syndrome/complications , Ventricular Function, Left , Ventricular Function, Right , Adolescent , Age Factors , Biomarkers/blood , COVID-19/diagnosis , COVID-19/immunology , Child , Cross-Sectional Studies , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/immunology , Echocardiography , Female , Heart Diseases/diagnostic imaging , Heart Diseases/immunology , Heart Diseases/physiopathology , Humans , Male , Prognosis , Retrospective Studies , Risk Assessment , Risk Factors , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/immunology
8.
Molecules ; 25(19)2020 Sep 24.
Article in English | MEDLINE | ID: covidwho-1302391

ABSTRACT

There is a vast practice of using antimalarial drugs, RAS inhibitors, serine protease inhibitors, inhibitors of the RNA-dependent RNA polymerase of the virus and immunosuppressants for the treatment of the severe form of COVID-19, which often occurs in patients with chronic diseases and older persons. Currently, the clinical efficacy of these drugs for COVID-19 has not been proven yet. Side effects of antimalarial drugs can worsen the condition of patients and increase the likelihood of death. Peptides, given their physiological mechanism of action, have virtually no side effects. Many of them are geroprotectors and can be used in patients with chronic diseases. Peptides may be able to prevent the development of the pathological process during COVID-19 by inhibiting SARS-CoV-2 virus proteins, thereby having immuno- and bronchoprotective effects on lung cells, and normalizing the state of the hemostasis system. Immunomodulators (RKDVY, EW, KE, AEDG), possessing a physiological mechanism of action at low concentrations, appear to be the most promising group among the peptides. They normalize the cytokines' synthesis and have an anti-inflammatory effect, thereby preventing the development of disseminated intravascular coagulation, acute respiratory distress syndrome and multiple organ failure.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Immunologic Factors/therapeutic use , Peptides/therapeutic use , Pneumonia, Viral/drug therapy , Respiratory System Agents/therapeutic use , Acute Disease , Anti-Inflammatory Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Betacoronavirus/drug effects , Betacoronavirus/growth & development , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Disseminated Intravascular Coagulation/complications , Disseminated Intravascular Coagulation/diagnosis , Disseminated Intravascular Coagulation/drug therapy , Disseminated Intravascular Coagulation/virology , Host-Pathogen Interactions/drug effects , Humans , Immunologic Factors/chemical synthesis , Lung/blood supply , Lung/drug effects , Lung/pathology , Lung/virology , Pandemics , Peptides/chemical synthesis , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Respiratory Insufficiency/complications , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/prevention & control , Respiratory Insufficiency/virology , Respiratory System Agents/chemical synthesis , SARS-CoV-2 , Structure-Activity Relationship
9.
PLoS One ; 16(6): e0253894, 2021.
Article in English | MEDLINE | ID: covidwho-1286873

ABSTRACT

OBJECTIVE: To describe the laboratory parameters and biomarkers of the cytokine storm syndrome associated with severe and fatal COVID-19 cases. METHODS: A search with standardized descriptors and synonyms was performed on November 28th, 2020 of the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, LILACS, and IBECS to identify studies of interest. Grey literature searches and snowballing techniques were additionally utilized to identify yet-unpublished works and related citations. Two review authors independently screened the retrieved titles and abstracts, selected eligible studies for inclusion, extracted data from the included studies, and then assessed the risk of bias using the Newcastle-Ottawa Scale. Eligible studies were those including laboratory parameters-including serum interleukin-6 levels-from mild, moderate, or severe COVID-19 cases. Laboratory parameters, such as interleukin-6, ferritin, hematology, C-Reactive Protein, procalcitonin, lactate dehydrogenase, aspartate aminotransferase, creatinine, and D-dimer, were extracted from the studies. Meta-analyses were conducted using the laboratory data to estimate mean differences with associated 95% confidence intervals. DATA SYNTHESIS: The database search yielded 9,620 records; 40 studies (containing a total of 9,542 patients) were included in the final analysis. Twenty-one studies (n = 4,313) assessed laboratory data related to severe COVID-19 cases, eighteen studies (n = 4,681) assessed predictors for fatal COVID-19 cases and one study (n = 548) assessed laboratory biomarkers related to severe and fatal COVID-19 cases. Lymphopenia, thrombocytopenia, and elevated levels of interleukin-6, ferritin, D-dimer, aspartate aminotransferase, C-Reactive-Protein, procalcitonin, creatinine, neutrophils and leucocytes were associated with severe and fatal COVID-19 cases. CONCLUSIONS: This review points to interleukin-6, ferritin, leukocytes, neutrophils, lymphocytes, platelets, C-Reactive Protein, procalcitonin, lactate dehydrogenase, aspartate aminotransferase, creatinine, and D-dimer as important biomarkers of cytokine storm syndrome. Elevated levels of interleukin-6 and hyperferritinemia should be considered as red flags of systemic inflammation and poor prognosis in COVID-19.


Subject(s)
Biomarkers/blood , COVID-19/pathology , Cytokine Release Syndrome/diagnosis , C-Reactive Protein/analysis , COVID-19/complications , COVID-19/mortality , COVID-19/virology , Cytokine Release Syndrome/etiology , Ferritins/blood , Humans , Interleukin-6/blood , Leukocytes/cytology , Leukocytes/metabolism , SARS-CoV-2/isolation & purification , Severity of Illness Index
10.
J Neuroimmunol ; 358: 577632, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1267756

ABSTRACT

SARS-CoV-2-induced COVID-19 is a serious pandemic of the 21st century, which has caused a devastating loss of lives and a global economic catastrophe. A successful vaccine against SARS-CoV-2 has suffered a delay due to lack of substantial knowledge about its mechanisms of action. Understanding the innate immune system against SARS-CoV-2 and the role of heat shock proteins' (HSP) inhibiting and resolution of inflammatory pathways may provide information to the low SARS-CoV-2 mortality rates in Africa. In addition, bats being a host to different viruses, including SARS-CoV-2 possess a well specialized IFN-innate antiviral inflammatory response, showing no signs of disease or pro-inflammatory cytokine storm. We discuss the molecular pathways in COVID-19 with a focus on innate immunity, inflammation, HSP responses, and suggest appropriate candidates for therapeutic targets and The contribution of the innate immune system to the efficacy of mRNA or vector based Corona immunizations.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Heat-Shock Proteins/immunology , Immunity, Innate/immunology , SARS-CoV-2/immunology , COVID-19/diagnosis , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/prevention & control , Humans , Immunity, Innate/drug effects , SARS-CoV-2/drug effects
11.
Virol J ; 18(1): 117, 2021 06 04.
Article in English | MEDLINE | ID: covidwho-1259206

ABSTRACT

BACKGROUND: To date, specific cytokines associated with development of acute respiratory distress syndrome (ARDS) and extrapulmonary multiple organ dysfunction (MOD) in COVID-19 patients have not been systematically described. We determined the levels of inflammatory cytokines in patients with COVID-19 and their relationships with ARDS and extrapulmonary MOD. METHODS: The clinical and laboratory data of 94 COVID-19 patients with and without ARDS were analyzed. The levels of inflammatory cytokines (interleukin 6 [IL-6], IL-8, IL-10, and tumor necrosis factor α [TNF-α]) were measured on days 1, 3, and 5 following admission. Seventeen healthy volunteers were recruited as controls. Correlations in the levels of inflammatory cytokines with clinical and laboratory variables were analyzed, furthermore, we also explored the relationships of different cytokines with ARDS and extrapulmonary MOD. RESULTS: The ARDS group had higher serum levels of all 4 inflammatory cytokines than the controls, and these levels steadily increased after admission. The ARDS group also had higher levels of IL-6, IL-8, and IL-10 than the non-ARDS group, and the levels of these cytokines correlated significantly with coagulation parameters and disseminated intravascular coagulation (DIC). The levels of IL-6 and TNF-α correlated with the levels of creatinine and urea nitrogen, and were also higher in ARDS patients with acute kidney injury (AKI). All 4 inflammatory cytokines had negative correlations with PaO2/FiO2. IL-6, IL-8, and TNF-α had positive correlations with the APACHE-II score. Relative to survivors, non-survivors had higher levels of IL-6 and IL-10 at admission, and increasing levels over time. CONCLUSIONS: The cytokine storm apparently contributed to the development of ARDS and extrapulmonary MOD in COVID-19 patients. The levels of IL-6, IL-8, and IL-10 correlated with DIC, and the levels of IL-6 and TNF-α were associated with AKI. Relative to survivors, patients who died within 28 days had increased levels of IL-6 and IL-10.


Subject(s)
COVID-19/blood , Cytokine Release Syndrome/blood , Cytokines/blood , Respiratory Distress Syndrome/blood , Acute Kidney Injury/diagnosis , Aged , Blood Urea Nitrogen , COVID-19/pathology , Creatinine/blood , Cytokine Release Syndrome/diagnosis , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/pathology , Female , Humans , Interleukin-10/blood , Interleukin-6/blood , Interleukin-8/blood , Male , Respiratory Distress Syndrome/pathology , Retrospective Studies , SARS-CoV-2 , Tumor Necrosis Factor-alpha/blood
12.
Nat Immunol ; 22(7): 829-838, 2021 07.
Article in English | MEDLINE | ID: covidwho-1220263

ABSTRACT

The innate immune response is critical for recognizing and controlling infections through the release of cytokines and chemokines. However, severe pathology during some infections, including SARS-CoV-2, is driven by hyperactive cytokine release, or a cytokine storm. The innate sensors that activate production of proinflammatory cytokines and chemokines during COVID-19 remain poorly characterized. In the present study, we show that both TLR2 and MYD88 expression were associated with COVID-19 disease severity. Mechanistically, TLR2 and Myd88 were required for ß-coronavirus-induced inflammatory responses, and TLR2-dependent signaling induced the production of proinflammatory cytokines during coronavirus infection independent of viral entry. TLR2 sensed the SARS-CoV-2 envelope protein as its ligand. In addition, blocking TLR2 signaling in vivo provided protection against the pathogenesis of SARS-CoV-2 infection. Overall, our study provides a critical understanding of the molecular mechanism of ß-coronavirus sensing and inflammatory cytokine production, which opens new avenues for therapeutic strategies to counteract the ongoing COVID-19 pandemic.


Subject(s)
COVID-19/immunology , Coronavirus Envelope Proteins/metabolism , Cytokine Release Syndrome/immunology , SARS-CoV-2/immunology , Toll-Like Receptor 2/metabolism , Animals , COVID-19/complications , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/virology , Chlorocebus aethiops , Cytokine Release Syndrome/diagnosis , Cytokines/metabolism , Disease Models, Animal , Female , Gene Expression Profiling , Humans , Immunity, Innate/drug effects , Leukocytes, Mononuclear , Macrophages , Male , Mice , Mice, Knockout , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Primary Cell Culture , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Severity of Illness Index , Signal Transduction/drug effects , Signal Transduction/genetics , Signal Transduction/immunology , Toll-Like Receptor 2/antagonists & inhibitors , Toll-Like Receptor 2/genetics , Vero Cells
13.
J Med Virol ; 93(9): 5474-5480, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1219314

ABSTRACT

In this study, laboratorial parameters of hospitalized novel coronavirus (COVID-19) patients, who were complicated with severe pneumonia, were compared with the findings of cytokine storm developing in macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis (sHLH). Severe pneumonia occurred as a result of cytokine storm in some patients who needed intensive care unit (ICU), and it is aimed to determine the precursive parameters in this situation. Also in this study, the aim is to identify laboratory criteria that predict worsening disease and ICU intensification, as well as the development of cytokine storm. This article comprises a retrospective cohort study of patients admitted to a single institution with COVID-19 pneumonia. This study includes 150 confirmed COVID-19 patients with severe pneumonia. When they were considered as severe pneumonia patients, the clinic and laboratory parameters of this group are compared with H-score criteria. Patients are divided into two subgroups; patients with worsened symptoms who were transferred into tertiary ICU, and patients with stable symptoms followed in the clinic. For the patients with confirmed COVID-19 infection, after they become complicated with severe pneumonia, lymphocytopenia (55.3%), anemia (12.0%), thrombocytopenia (19.3%), hyperferritinemia (72.5%), hyperfibrinogenemia (63.7%) and elevated lactate dehydrogenase (LDH) (90.8%), aspartate aminotransaminase (AST) (31.3%), alanine aminotransaminase (ALT) (20.7%) are detected. There were no significant changes in other parameters. Blood parameters between the pre-ICU period and the ICU period (in which their situation had been worsened and acute respiratory distress syndrome [ARDS] was developed) were also compared. In the latter group lymphocyte levels were found significantly reduced (p = 0.01), and LDH, highly sensitive troponin (hs-troponin), procalcitonin, and triglyceride levels were significantly increased (p < 0.05). In addition, there was no change in hemoglobin, leukocyte, platelet, ferritin, and liver function test levels, including patients who developed ARDS, similar to the cytokine storm developed in MAS/sHLH. COVID-19 pneumonia has similar findings as hyperinflammatory syndromes but does not seem to have typical features as in cytokine storm developed in MAS/sHLH. In the severe patient group who has started to develop ARDS signs, a decrease in lymphocyte level in addition to the elevated LDH, hs-troponin, procalcitonin, and triglyceride levels can be a predictor in progression to ICU admission and could help in the planning of anti-cytokine therapy.


Subject(s)
COVID-19/pathology , Cytokine Release Syndrome/pathology , Lymphohistiocytosis, Hemophagocytic/pathology , Macrophage Activation Syndrome/pathology , SARS-CoV-2/pathogenicity , Aged , Alanine Transaminase/blood , Anemia/blood , Anemia/diagnosis , Anemia/immunology , Anemia/pathology , Aspartate Aminotransferases/blood , Biomarkers/blood , COVID-19/blood , COVID-19/diagnosis , COVID-19/immunology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/immunology , Diagnosis, Differential , Disease Progression , Female , Fibrinogen/metabolism , Humans , Hyperferritinemia/blood , Hyperferritinemia/diagnosis , Hyperferritinemia/immunology , Hyperferritinemia/pathology , Intensive Care Units , L-Lactate Dehydrogenase/blood , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/immunology , Lymphopenia/blood , Lymphopenia/diagnosis , Lymphopenia/immunology , Lymphopenia/pathology , Macrophage Activation Syndrome/blood , Macrophage Activation Syndrome/diagnosis , Macrophage Activation Syndrome/immunology , Male , Middle Aged , Procalcitonin/blood , Retrospective Studies , Thrombocytopenia/blood , Thrombocytopenia/diagnosis , Thrombocytopenia/immunology , Thrombocytopenia/pathology , Triglycerides/blood , Troponin/blood
14.
Eur J Immunol ; 51(8): 2074-2085, 2021 08.
Article in English | MEDLINE | ID: covidwho-1212744

ABSTRACT

The aberrant release of inflammatory mediators often referred to as a cytokine storm or cytokine release syndrome (CRS), is a common and sometimes fatal complication in acute infectious diseases including Ebola, dengue, COVID-19, and influenza. Fatal CRS occurrences have also plagued the development of highly promising cancer therapies based on T-cell engagers and chimeric antigen receptor (CAR) T cells. CRS is intimately linked with dysregulated and excessive cytokine release, including IFN-γ, TNF-α, IL 1, IL-6, and IL-10, resulting in a systemic inflammatory response leading to multiple organ failure. Here, we show that mice intravenously administered the agonistic hamster anti-mouse CD3ε monoclonal antibody 145-2C11 develop clinical and laboratory manifestations seen in patients afflicted with CRS, including body weight loss, hepatosplenomegaly, thrombocytopenia, increased vascular permeability, lung inflammation, and hypercytokinemia. Blood cytokine levels and gene expression analysis from lung, liver, and spleen demonstrated a hierarchy of inflammatory cytokine production and infiltrating immune cells with differentiating organ-dependent kinetics. IL-2, IFN-γ, TNF-α, and IL-6 up-regulation preceded clinical signs of CRS. The co-treatment of mice with a neutralizing anti-cytokine antibody cocktail transiently improved early clinical and laboratory features of CRS. We discuss the predictive use of this model in the context of new anti-cytokine strategies to treat human CRS.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antibodies/immunology , CD3 Complex/antagonists & inhibitors , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/metabolism , Cytokines/antagonists & inhibitors , Cytokines/metabolism , Animals , Antibodies/adverse effects , Antibodies, Monoclonal/therapeutic use , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/drug therapy , Cytokines/blood , Disease Models, Animal , Drug Therapy, Combination , Inflammation Mediators/blood , Inflammation Mediators/metabolism , Lymphocyte Activation/immunology , Mice , Phenotype , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Treatment Outcome
15.
J Med Virol ; 93(3): 1672-1677, 2021 03.
Article in English | MEDLINE | ID: covidwho-1206819

ABSTRACT

While the number of coronavirus disease-2019 (COVID-19) cases is increasing day by day, there is limited information known about the hematological and laboratory findings of the disease. We aimed to investigate whether serum ferritin level predicts mortality is a marker for rapid progression for inpatients. Our study included 56 patients who were died due to COVID-19 as the study group, and 245 patients who were hospitalized and recovered as the control group. The laboratory data of the patients were evaluated from the first blood tests (pre) taken from the first moment of admission to the hospital and the blood tests taken from before the patient's discharge or exitus (post) were evaluated retrospectively. The mean age of the nonsurvivor group was 62.0 ± 15.7 and the mean age of the control group was 54.34 ± 13.03. Age and length of stay are significantly higher in the nonsurvivor group. When comparing the pre- and postvalues of ferritin, according to the two groups separately, there was no significant difference in the control group and a high level of significance was observed in the nonsurvivor group (p < .01). COVID-19 disease caused by severe acute respiratory syndrome coronavirus-2 causes high mortality with widespread inflammation and cytokine storm. Ferritin is a cheap and widespread available marker, ferritin, which can be used for its predictivity of the mortality and hope it would be a useful marker for clinicians for the management of the disease.


Subject(s)
COVID-19/blood , COVID-19/mortality , Cytokine Release Syndrome/mortality , Ferritins/blood , Amides/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/diagnosis , Female , Hospitalization , Humans , Length of Stay , Male , Middle Aged , Prognosis , Pyrazines/therapeutic use , SARS-CoV-2 , Severity of Illness Index
16.
Cytokine Growth Factor Rev ; 58: 32-48, 2021 04.
Article in English | MEDLINE | ID: covidwho-1163617

ABSTRACT

The coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), appears with a wide spectrum of mild-to-critical clinical complications. Many clinical and experimental findings suggest the role of inflammatory mechanisms in the immunopathology of COVID-19. Hence, cellular and molecular mediators of the immune system can be potential targets for predicting, monitoring, and treating the progressive complications of COVID-19. In this review, we assess the latest cellular and molecular data on the immunopathology of COVID-19 according to the pathological evidence (e.g., mucus and surfactants), dysregulations of pro- and anti-inflammatory mediators (e.g., cytokines and chemokines), and impairments of innate and acquired immune system functions (e.g., mononuclear cells, neutrophils and antibodies). Furthermore, we determine the significance of immune biomarkers for predicting, monitoring, and treating the progressive complications of COVID-19. We also discuss the clinical importance of recent immune biomarkers in COVID-19, and at the end of each section, recent clinical trials in immune biomarkers for COVID-19 are mentioned.


Subject(s)
Biomarkers/blood , COVID-19/diagnosis , COVID-19/therapy , Immunity, Innate/physiology , Monitoring, Physiologic/methods , Biomarkers/analysis , COVID-19/blood , COVID-19/complications , Chemokines/analysis , Chemokines/blood , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/therapy , Cytokines/analysis , Cytokines/blood , Humans , Prognosis , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/therapy , SARS-CoV-2/physiology
17.
Iran J Immunol ; 18(1): 54-64, 2021 03.
Article in English | MEDLINE | ID: covidwho-1160833

ABSTRACT

BACKGROUND: SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is recognized for the first time in Wuhan, China. The cytokine storm is a known factor causing major clinical symptoms leading to death in COVID-19 patients. OBJECTIVE: To investigate and compare the serum levels of different cytokines in COVID-19 patients with different clinical severity. METHODS: Concentrations of serum cytokines, including IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ, and GM-CSF, were measured in 61 COVID-19 patients and 31 normal controls with ELISA. We investigated the correlation between the levels of these cytokines and clinical severity, CRP level, neutrophil and lymphocyte count in patients with COVID-19. RESULTS: Our data indicated that the levels of IL-1ß, IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF, but not IL-10 were significantly increased in COVID-19 patients compared to normal controls. Statistical analysis showed that the level of IL-1ß, IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF were higher in severe COVID-19 than those of mild cases. The concentrations of all mentioned cytokines were negatively associated with the absolute count of lymphocytes, and positively correlated with the CRP level and the absolute count of neutrophils. CONCLUSION: The current study suggests that high levels of various cytokines correlate with the disease severity and immunopathogenesis of COVID-19.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Cytokines/blood , SARS-CoV-2/immunology , Aged , Biomarkers/blood , C-Reactive Protein/analysis , COVID-19/blood , COVID-19/diagnosis , COVID-19/virology , Case-Control Studies , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/virology , Female , Host-Pathogen Interactions , Humans , Iran , Lymphocytes/immunology , Lymphocytes/metabolism , Lymphocytes/virology , Male , Middle Aged , Neutrophils/immunology , Neutrophils/metabolism , Neutrophils/virology , SARS-CoV-2/pathogenicity , Severity of Illness Index
18.
Vascul Pharmacol ; 138: 106857, 2021 06.
Article in English | MEDLINE | ID: covidwho-1144980

ABSTRACT

COVID-19 is a pandemic illness caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). It has been estimated that 80% of subject infected are asymptomatic or have mild to moderate symptoms. Differently, in severe cases of COVID-19, cytokine storm, acute respiratory distress syndrome (ARDS), severe systemic inflammatory response and cardiovascular diseases were observed Even if all molecular mechanisms leading to cardiovascular dysfunction in COVID-19 patients remain to be clarified, the evaluation of biomarkers of cardiac injury, stress and inflammation proved to be an excellent tool to identify the COVID-19 patients with worse outcome. However, the number of biomarkers used to manage COVID-19 patients is expected to increase with the increasing knowledge of the pathophysiology of the disease. It is our view that soluble suppressor of tumorigenicity 2 (sST2) can be used as biomarker in COVID-19. sST2 is routinely used as prognostic biomarker in patients with HF. Moreover, high circulating levels of sST2 have also been found in subjects with ARDS, pulmonary fibrosis and sepsis. Keeping in mind these considerations, in this review the possible mechanisms through which the SARS-CoV2 infection could damage the cardiovascular system were summarized and the possible role of sST2 in COVID-19 patients with CVD was discussed.


Subject(s)
COVID-19/epidemiology , COVID-19/metabolism , Cytokine Release Syndrome/epidemiology , Cytokine Release Syndrome/metabolism , Interleukin-1 Receptor-Like 1 Protein/metabolism , Animals , Biomarkers/metabolism , COVID-19/diagnosis , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/metabolism , Cytokine Release Syndrome/diagnosis , Humans , Prognosis
20.
Transl Res ; 232: 1-12, 2021 06.
Article in English | MEDLINE | ID: covidwho-1118707

ABSTRACT

Although interest in "cytokine storms" has surged over the past decade, it was massively amplified in 2020 when it was suggested that a subset of patients with COVID-19 developed a form of cytokine storm. The concept of cytokine storm syndromes (CSS) encompasses diverse conditions or circumstances that coalesce around potentially lethal hyperinflammation with hemodynamic compromise and multiple organ dysfunction syndrome. Macrophage activation syndrome (MAS) is a prototypic form of CSS that develops in the context of rheumatic diseases, particularly systemic juvenile idiopathic arthritis. The treatment of MAS relies heavily upon corticosteroids and cytokine inhibitors, which have proven to be lifesaving therapies in MAS, as well as in other forms of CSS. Within months of the recognition of SARS-CoV2 as a human pathogen, descriptions of COVID-19 patients with hyperinflammation emerged. Physicians immediately grappled with identifying optimal therapeutic strategies for these patients, and despite clinical distinctions such as marked coagulopathy with endothelial injury associated with COVID-19, borrowed from the experiences with MAS and other CSS. Initial reports of patients treated with anti-cytokine agents in COVID-19 were promising, but recent large, better-controlled studies of these agents have had mixed results suggesting a more complex pathophysiology. Here, we discuss how the comparison of clinical features, immunologic parameters and therapeutic response data between MAS and hyperinflammation in COVID-19 can provide new insight into the pathophysiology of CSS.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/etiology , Macrophage Activation Syndrome/etiology , SARS-CoV-2 , COVID-19/immunology , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/therapy , Humans , Macrophage Activation Syndrome/diagnosis , Macrophage Activation Syndrome/therapy
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